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Cancers have a mutator phenotype [1]. An elevated mutation rate is central to tumorigenesis in human malignancies and significantly contributes to the disruption of regulatory processes essential to genomic stability. Endometrial cancers (ECs) are frequently defective in DNA mismatch repair (MMR). Reduced post-replication surveillance and repair results in a 100-fold increase in somatic mutations in human tumor cell lines [2]. Recently, loss of DNA proofreading function in the DNA polymerase e (POLE) has similarly been shown to be important in tumorigenesis in EC. Approximately 7% of ECs harbor mutations in the exonuclease domain of POLE [3, 4]. POLE encodes the major catalytic and proofreading subunits of the Pole DNA polymerase enzyme complex [5]. The Pole enzyme complex synthesizes the leading strand [5-8]. The proofreading (exonuclease) function locates and replaces erroneous bases in the daughter strand through failed complementary pairing with the parental strand. High fidelity incorporation of bases by POLE, coupled with its exonuclease proofreading function ensures a low mutation rate. POLE exonuclease domain mutations (EDMs) have shown to increase spontaneous mutation rates contributing to tumorigenesis in yeast and mouse models [9-14]. The Cancer Genome Atlas (TCGA) reported a POLE mutant subtype of EC [3]. Tumors with POLE EDMs are referred to as “POLE ultra-mutated”. ECs in this molecularly defined group are of endometrioid histology, predominantly have normal DNA MMR (microsatellite stable (MSS)) and have thousands of somatic mutations. Clinically, patients in the POLE ultra-mutated group were reported to have improved progression-free survival (PFS) [3]. We undertook an analysis of POLE mutations in a large cohort of endometrioid ECs to better understand clinicopathologic significance of POLE EDMs.

DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC.Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided.Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 (MLH1) methylation (P.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127).The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing.